Genomic Bookmarks Uncovered

First Chapter of Human Epigenome Project

Genomic Bookmarks Uncovered

Somewhere, we all have a textbook from school with pencilled notes in the margin which tell us which bits should be
remembered and which bits we can forget. Sometimes, we change our minds and erase the notes, or add new ones. Our
friends make different notes and remember different key passages.

The 'Book of Life' - the human genome - carries equivalent marks on the letters of DNA code - chemical marks that help
our cells to know which bits should be active and which bits are not to be used.

For our genome to function correctly, sequence alone is not sufficient. It is marked by addition of methyl groups to
cytosine bases in DNA. As well as altering activity of genes, methylation of DNA can have consequences for development
and diseases such as cancer.

Apart from a few genes, the methylation profile of human DNA is poorly understood but, with completion of the Human Genome Project, it now becomes possible to determine the effects of
methylation on a global, genome-wide scale. The goal of the Human Epigenome Project (HEP), a collaboration between The
Wellcome Trust Sanger Institute, Epigenomics AG and The Centre National de Génotypage, is to define methylation
on a scale never attempted before and to investigate fully its role in health and disease.

The Pilot study for the HEP - the first systematic analysis of methylation - is published on Tuesday 23 November 2004
in PLoS
Biology. The Consortium proved that their novel approach is highly successful in detecting these subtle changes and
that differences between individuals and tissues samples can be readily detected. The systems are now in place to
complete the first study of the entire human epigenome.

"Application of high-throughput analysis to detect subtle changes like those found in methylation
was a tremendously challenging task," said Dr Stephan Beck, the Project's Principal Investigator at The Wellcome
Trust Sanger Institute, "but the MHC is an ideal model for understanding the entire human
epigenome. In a very short time, we have moved these technologies from testing grounds to a position of being able to
tackle the entire genome and get detailed and global understanding of the role that methylation plays in health and
disease."

The team have focused on a region of the genome that is involved many diseases and is rich in genes - the Major
Histocompatability Complex (MHC). As well as a role in the immune system, the MHC is also involved in diseases from
diabetes to arthritis.

Regions of genes and regions that control genes were studied using two techniques: there is existing evidence that
methylation of control regions modifies the activity of the affected gene. Looking at more than 250 regions of 90 genes
(about 0.4% of all human genes), both methods showed that, most often, the samples either had very little methylation
or were almost fully methylated.

"The Human Genome Project has produced the foundation for new biomedical research. Our challenge as
scientists is to translate that knowledge into real benefit. The epigenome is a key to unlocking the secrets of many
diseases," said Dr Kurt Berlin, the Project's Principal Investigator and Chief Scientific Officer at Epigenomics
AG. "Already our results indicate intriguing levels of variation in the human epigenome and with
the continued production of results new ways to look at genes and disease are emerging."

Specific differences in methylation were found among tissues and individuals. For example, a gene called TNXB involved
in limb, heart and muscle development was methylated in most tissues except muscle, suggesting lack of methylation is
important for the activity of TNXB in this tissue. However, the study suggests that, for many genes, we need a better
understanding of their activity, a major focus of projects at The Wellcome Trust Sanger Institute and other
institutions.

Across the range of tissues tested, high levels of methylation at predicted control regions were correlated with low
levels of gene activity and high gene activity correlated with low levels of methylation. The Pilot phase has
established that bases of DNA code that are subject to different levels of methylation in different tissues or
different individuals can be detected in a systematic fashion.

From now, it becomes possible truly to examine the role of methylation in gene activity and, most important, in human
disease such as cancer where there is already evidence that methylation plays a role in disease and prognosis.

Phase I of the HEP, based on the findings reported today, is already underway to analyse some 10% of all human genes,
using 20 tissue types from more than 40 people.

Methylation changes have been found in a wide range of diseases including:

Notes to Editors

About the HEP

The Human Epigenome Project (HEP) aims to identify, catalogue and interpret genome-wide DNA methylation patterns of
all human genes in all major tissues. Methylation is the only flexible genomic parameter that can change genome
function under exogenous influence. Hence it constitutes the main and so far missing link between genetics, disease
and the environment that is widely thought to play a decisive role in the aetiology of virtually all human
pathologies. Methylation occurs naturally on cytosine bases at CpG sequences and is involved in controlling the
correct expression of genes. Differentially methylated cytosines give rise to distinct patterns specific for tissue
type and disease state. Such methylation variable positions (MVPs) are common epigenetic markers. Like single
nucleotide polymorphisms (SNPs), they promise to significantly advance our ability to understand and diagnose human
disease.

The Human Epigenome Project (HEP) is a public/private collaboration run by the members of the Human Epigenome
Consortium. MVPs identified as part of the HEP will be released publicly in accordance with the HEP data release
policy.

The Wellcome Trust Sanger Institute, a recognised leader in genome sequencing, high-throughput
systems, informatics and analysis of gene function using genetic approaches in a variety of model organisms and
humans.

Epigenomics AG, a transatlantic biotechnology company with
headquarters in Berlin, Germany and its wholly owned subsidiary in Seattle, Washington, USA. Epigenomics AG is
pioneering tomorrow's personalized medicine by exploiting the information of DNA methylation patterns.

The Centre National de Génotypage, a national research institute set up
in 1998 by the French Government in anticipation of using the genome sequencing information for the
identification of genes and gene function.

Publication details

DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project.

Websites

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

Websites

The Wellcome Trust and Its Founder

The Wellcome
Trust is the most diverse biomedical research charity in the
world, spending about £450 million every year both in the UK
and internationally to support and promote research that will
improve the health of humans and animals. The Trust was established
under the will of Sir Henry
Wellcome, and is funded from a private endowment, which is
managed with long-term stability and growth in mind.